1. Field of the Invention
The present invention relates to a process for preparing nitrogen-substituted aminotetralins. Particularly, the invention relates to the alkylation of 2-aminotetralins wherein the alkylation is performed in the presence of a base selected from the group consisting of alkali metal carbonate or alkali metal bicarbonate, and wherein the amount of the base is less than about a 1.9-fold molar excess with respect to the starting material.
2. Related Art
A variety of conventional synthetic methods have been used to prepare nitrogen-substituted 2-aminotetralins included in the following Formula (I): 
wherein R1 is OA; R2 is selected from the group consisting of H and OA; A is H or is selected from the group consisting of hydrocarbyl radicals comprising between 1 and 3 carbon atoms, as well as one of the following radicals 
wherein R5 is selected from the group consisting of alkyl and aromatic residues having from 1 to 20 carbon atoms; R3 is selected from the group consisting of alkoxy, cycloalkoxy, optionally substituted phenyl, 3-pyridyl, 4-pyridyl, 
where X is S, O or NH; R4 is an unbranched alkyl chain having from 1 to 3 carbon atoms; and n is an integer from 1 to 5.
For example, Horn, A. S., et al., Pharmaceutisch Weekblad Sci. Ed. 7:208-211 (1985) describes a reductive amination wherein 2-(N-n-propylamino)-5-methoxytetralin and 2-thiopheneacetic acid are reacted in the presence of trimethylaminoborohydride to produce 2-(N-n-propyl-N-2-thienylethylamino)-5-methoxytetralin. The product is further reacted with a solution of BBr3 to produce 2-(N-n-propyl-N-2-thienylethylamino)-5-hydroxytetralin. The reaction scheme can be presented as follows, wherein n is 2, R4 is n-propyl and R3 is thienyl: 
U.S. Pat. No. 5,382,596 describes an alkylation reaction of the following scheme wherein R4 is an unbranched alkyl chain comprising from 1 to 3 carbon atoms or a cyclopropylmethyl radical and R6 is xe2x80x94(CH2)nxe2x80x94R3, wherein n is an integer from 1 to 4 and R3 is alkoxy, cycloalkoxy or a cyclic ether: 
U.S. Pat. No. 4,410,519 describes the following alkylation reaction, wherein R4 is alkyl of 1 to 4 carbon atoms, A is xe2x80x94(CH2)nxe2x80x94, wherein n is 1 to 5 and Z is a leaving group, preferably chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy: 
In the above reaction, the presence of the base is optional and it may be, e.g., a tertiary amine or an alkali metal carbonate or bicarbonate.
Conventional alkylation reactions produce acidic by-products from the leaving groups within the alkylating agents employed. If these acidic by-products are not neutralized, the progress of the reaction is frequently harmed either by: (a) the starting material, i.e., the amine, serving as an acid scavenger and precipitating from solution, thereby terminating the reaction, or (b) the acidic by-products degrading the starting material and/or alkylating agent, thereby terminating the reaction or producing increased amounts of impurities. In order to avoid these problems, such alkylations typically employ a large excess of base, commonly greater than two-fold molar excess with respect to the starting material.
The conventional alkylation methods described above suffer from limited product yields resulting from incomplete reactions and inefficient purification procedures required to reduce the levels of impurities. Nitrogen-substituted 2-aminotetralins are useful as pharmaceutical agents that treat a number of diseases and, therefore, product purity is a major concern. Attempts are being made to improve yields and to efficiently produce more pure products. Manufacturing problems are particularly acute when very expensive chiral starting materials are used. It can be readily seen that even minor improvements in process efficiency will result in economic benefits. This is particularly true upon scaleup manufacture of chirally pure products. A need therefore exists for processes of synthesis having improved yields, shorter reaction times and purer products.
Alkali metal carbonates and alkali metal bicarbonates are used as acid scavengers in alkylation reactions that attach substituents on the nitrogen atom in 2-aminotetralins. It has now been discovered that the amount of alkali metal carbonate or alkali metal bicarbonate used in these alkylation reactions is a critically important factor in the course of the reaction. Applicants found that the amount of alkali metal carbonate or alkali metal bicarbonate should be less than about a 1.9-fold molar excess with respect to the 2-aminotetralin starting material.
It has been discovered that the use of limited amounts of alkali metal carbonate or alkali metal bicarbonate in these reactions gives a more efficient process for preparing N-substituted 2-aminotetralins than the prior art processes used for preparing these compounds, allowing the production of more pure products and, thus, avoiding extensive purification procedures. Accordingly, the present invention provides a process for preparing 2-aminotetralins of the Formula (I): 
wherein R1 is OA; R2 is selected from the group consisting of H and OA; A is H or is selected from the group consisting of a straight or a branched alkyl chain having from 1 to 3 carbon atoms, 
wherein R5 is selected from the group consisting of C1-C20 alkyl, C6-C10 aryl and C7-C20arylalkyl; R3 is selected from the group consisting of alkoxy, cycloalkoxy, optionally substituted phenyl, 3-pyridyl, 4-pyridyl, 
where X is S, O or NH; R4 is an unbranched alkyl chain having from 1 to 3 carbon atoms; and n is an integer from 1 to 5.
The process comprises allowing a 2-aminotetralin of Formula (II): 
wherein R1, R2 and R4 are as defined above, to react with a reactant of Formula (III):
Zxe2x80x94(CH2)nxe2x80x94R3xe2x80x83xe2x80x83(III)
wherein R3 and n are as defined above and Z is a leaving group, in the presence of a base, wherein the base is selected from the group consisting of alkali metal carbonate and alkali metal bicarbonate, and wherein the amount of the base is less than about a 1.9-fold molar excess with respect to the amount of the 2-aminotetralin.
Preferably, from about 0.2 to about 1.8 mole ratio, more preferably from about 0.2 to about 1.5 mole ratio, more preferably from about 0.3 to about 1.3 mole ratio of alkali metal carbonate or alkali metal bicarbonate with respect to the 2-aminotetralin starting material is used. Especially, from about 0.3 to about 1.0 mole ratio, more especially from about 0.4 to 0.8 mole ratio, specifically from about 0.4 to about 0.7 mole ratio, of alkali metal carbonate or alkali metal bicarbonate with respect to the 2-aminotetralin starting material is used as an acid scavenger.
Further, the present invention provides an improvement in a method of alkylating 2-aminotetralin of Formula (II), wherein R1, R2 and R4 are as defined above, with a reactant of Formula (III), wherein R3 and n are as defined above and Z is a leaving group, in the presence of a base, the improvement comprising employing abase selected from the group consisting of alkali metal carbonate and alkali metal bicarbonate, wherein the amount of the base is less than about a 1.9-fold molar excess with respect to the amount of the 2-aminotetralin.
Additional embodiments and advantages of the invention will be set forth in part in the description as follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
Applicants found that by reducing the amount of base in a process for preparing nitrogen-substituted 2-aminotetralins of Formula (I) the amount of by-products was essentially decreased and, thus, more pure products were achieved. It was discovered that less than about a 1.9-fold molar excess of an alkali metal carbonate or an alkali metal bicarbonate with respect to the amine starting material is an ideal amount to be used as an acid scavenger. The products of Formula (I) can be optically active or racemic.
The reaction scheme of the process according to the invention can be presented as follows: 
In the above formulae, R1 is OA; R2 is selected from the group consisting of H and OA; A is H or is selected from the group consisting of a straight or a branched alkyl chain having from 1 to 3 carbon atoms, 
wherein R5 is selected from the group consisting of C1-C20 alkyl, C6-C10 aryl and C7-C20arylalkyl; R3 is selected from the group consisting of alkoxy, cycloalkoxy, optionally substituted phenyl, 3-pyridyl, 4-pyridyl, 
where X is S, O or NH; R4 is an unbranched alkyl chain having from 1 to 3 carbon atoms; n is an integer from 1 to 5; and Z is a leaving group.
A is preferably H, CH3 or xe2x80x94C(O)xe2x80x94R5, most preferably hydrogen.
Preferably R5 is selected from the group of C1-C12 alkyl, C6-C10 aryl and C7-C12arylalkyl, such as phenyl, methyl, tertiary butyl, methylphenyl, o-, m-, or p-methoxyphenyl.
Preferably, R3 is selected from the group consisting of phenyl, hydroxyphenyl, thienyl, especially 2-thienyl and 3-thienyl, and alkoxy. Preferably, alkoxy is selected from the group consisting of ethoxy, propoxy, isopropoxy, butoxy, secondary butoxy, isobutoxy, and tertiary butoxy.
In the more preferred compounds, R2 is H and n is an integer from 1 to 3.
Z is preferably chlorine, bromine, iodine, alkylsulfonyloxy, such as trifluoromethylsulfonyloxy, or arylsulfonyloxy, such as benzenesulfonyloxy or toluenesulfonyloxy.
Alkyl means straight or branched hydrocarbon alkyl having 1 to 20 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, and eicosyl.
Alkoxy means straight-chain or branched alkoxy having 1 to 5 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, secondary butoxy, tertiary butoxy, pentyloxy, and isopentyloxy.
Cycloalkoxy means a cycloalkyl group with a single covalent bond to an oxygen atom where the cycloalkyl moiety is a cyclic alkyl group having 3 to 6 carbon atoms.
Aryl means phenyl or naphthyl or substituted phenyl or substituted naphthyl which are phenyl or naphthyl substituted by at least one substituent selected from the group consisting of halogen (chlorine, bromine, fluorine, or iodine), amino, nitro, hydroxy, and alkyl.
A preferred compound produced by the process according to the invention is (xe2x88x92)-5-hydroxy-2-[N-n-propyl-N-2-(2-thienyl)ethylamino]tetralin.
Preferably, from about 0.2 to about 1.8 mole ratio, more preferably from about 0.2 to about 1.5 mole ratio, more preferably from about 0.3 to about 1.3 mole ratio of alkali metal carbonate or alkali metal bicarbonate with respect to the 2-aminotetralin starting material is used. Especially, from about 0.3 to about 1.0 mole ratio, more especially from about 0.4 to 0.8 mole ratio, specifically from about 0.4 to about 0.7 mole ratio, of alkali metal carbonate or alkali metal bicarbonate with respect to the 2-aminotetralin starting material is used as an acid scavenger.
Preferably, the alkali metal carbonate is sodium carbonate and the alkali metal bicarbonate is sodium bicarbonate. Other useful bases include potassium carbonate and potassium bicarbonate.
Preferably, the reactant is Zxe2x80x94(CH2)nxe2x80x94R3, wherein Z, n and R3 are as defined above. Useful reactants include 2-(2-thienyl)ethanol benzenesulfonate and 2-(2-thienyl)ethanol toluenesulfonate.
The decreased amounts of alkali metal carbonate or alkali metal bicarbonate in the process according to the invention allow the production of more pure products without the requirement of extensive purification procedures. Further, this way of minimizing the production of by-products allows the addition of additional alkylating reactant in order to accelerate the completion of the reaction without incurring an unacceptably complex product mixture. The resultant savings in reaction time constitutes a significant advantage when costly large scale manufacturing equipment is employed.
Table 1 below shows clearly that the conventionally-used large excess of alkali metal carbonate or bicarbonate, i.e., greater than a two-fold molar excess with respect to the starting material, results in reaction mixtures containing undesirable amounts of impurities that complicate attempts at product isolation. Further, the reaction time is substantially longer when a large excess of the base is used.
The process of the invention may be conveniently effected at temperatures from about 90xc2x0 C. to about 180xc2x0 C., preferably from about 110xc2x0 C. to about 145xc2x0 C.
The starting materials, e.g., the compounds of Formula (II) and (III), are either known or may be produced in known manner or analogous to the methods described herein. For example, the 2-aminotetralin starting materials can be prepared as described in U.S. Pat. Nos. 4,968,837 and 4,564,628. Optically active compounds may be produced from optically active starting materials.